RU2257890C2 - Method for preparing stable pharmaceutical compositions in omeprazole-containing tablet formulation and pharmaceutical composition prepared by this method - Google Patents

Abstract

FIELD: chemical-pharmaceutical industry and technology, pharmacy.

SUBSTANCE: omeprazole is a strong anti-ulcer agent that is absorbed in intestine preferably but it unstable in acid medium. Some methods for preparing stable pharmaceutical compositions and solution of two main problems of effect on their stability, pH and moisture, have been studied. Invention describes a method for preparing pharmaceutical composition as tablet formulation comprising omeprazole, sodium alginate and basic amino acid and involving following steps: (a) preliminary modification of external morphology of basic amino acid by wetting and the following drying up to the water content in the total amount less 0.75 wt.-% of amino acid mass; (b) incorporation of basic amino acid to preliminary prepared granulate comprising omeprazole and sodium alginate with the low moisture content; (c) incorporation of other excipients up to preparing granulate; (d) grinding granulate from step (c) up to preparing uniform granulometric composite; (e) incorporation of lubricating agent, carrying out the tableting process and applying enterosoluble coating on tablets made. Such method is simpler as compared with known ones and provides preparing compositions with improved indices of extrusion. The content of sodium alginate can up to 15 wt.-% of tablet mass, preferably, from 8 to 12 wt.-%. Basic amino acid can represent L-arginine, L-lysine or L-histidine. Pharmaceutical compositions prepared by this method comprise omeprazole in concentrations 10-40 mg per a tablet.

EFFECT: improved preparing method.

6 cl, 4 ex

Description

Description

The present invention relates to a method for producing stable tablets with omeprazole and its salts having satisfactory pharmaceutical properties and stability. The invention also relates to pharmaceutical compositions in tablets obtained in this way.

Omeprazole is a potent antiulcer drug that is preferably absorbed in the intestine and reduces acid secretion in the stomach by selectively inhibiting the P + / K + ATPase enzyme located in the intercellular tubules of parietal cells (LANCET-Nov.27, 1982, pp.1123-1124 )

Omeprazole is unstable in an acidic environment (Pilbrant and Cederberg, Scand. J. Gastroenterology (1985), 20 (Suppl. 108), pp. 113-120), (Lindberg Per et al., J. Med. Chem. (1986), 29, pp. 1327-1329). The half-life of decomposition in water and at pH 7 is less than 10 minutes, being equal to about 14 hours at a pH of about 7.

A number of options have been investigated with the goal of producing stable pharmaceutical compositions. The main task is to solve two main problems (pH and moisture), activating the stability of omeprazole.

So, for example, in British patent GB No. 218969 (1987) describes the preparation of an oral form of omeprazole, characterized by the presence of a core formed by an active ingredient (omeprazole) with alkaline properties, and applied to the core of the coating from one or more protective layers, soluble in water, and having an outer layer of enteric coating. The method and the products obtained therefrom showed suitable resistance to gastric juice and good stability of the active element (omeprazole) contained in them in the gastric juice, as well as during storage for a long time.

US Pat. No. 4,786,505 (1988) describes the preparation of oral compositions containing omeprazole characterized by the presence in the core of an alkaline compound together with the active ingredient. The core is coated with a sublayer formed by a water-soluble substance or a substance that rapidly decomposes in the presence of water and an outer enteric layer.

US Pat. No. 5,690,960 (1977) also describes a method for preparing a stable oral form characterized by the presence of omeprazole magnesium salt in a core, on which two layers are applied, one of which is capable of decomposing in an aqueous medium, and the second layer is enteric.

US Pat. No. 5,232,706 (1993) describes the preparation of a core with two coating layers. The first layer is formed from soluble excipients and compounds similar to basic amino acids, and the second layer is an enteric coating. Both layers are intended to protect omeprazole from exposure to acidic environment and moisture.

The above methods and other methods described in the patent literature, although they make it possible to obtain suitable pharmaceutical agents (tablets / capsules), demonstrate a number of practical inconveniences, for example, described below.

1. Obtaining a pharmaceutical mixture for oral administration (tablets or capsules) requires the implementation of several stages:

a) obtaining a core or granules with the active ingredient or its salt, and in some cases, the main substances are included in said core;

b) coating the core with the formation of a sublayer that readily decomposes in an aqueous medium, for example, in a fluidized bed;

c) applying an enteric coating to the granule or core and drying it;

d) finally, performing tabletting or encapsulation, respectively.

2. Each process for its implementation requires the use of various equipment, such as, for example, a mixer, a fluidized bed installation, tabletting or encapsulating machines, or other equipment.

3. As a rule, due to the instability of the easily hydrolyzable drug and the presence of a sublayer of hydrophilic water-soluble coating, it is necessary to carry out quick drying and to regulate humidity in the future.

4. The correct execution of each stage, both in the case of capsules and in the case of tablets, requires a significantly longer period of time than the time taken for the industrial production of the same pharmaceutical forms, but with other active ingredients.

Korean patent KR 115254 (1997), corresponding to the publication of application 95-15059 (1995), describes the use of basic amino acids to stabilize omeprazole. Some of them are L-arginine, L-lysine, its calcium salt, hydroxylisine and histidine, in a 15-25-fold molar excess, and stable preparations are obtained, bypassing the intermediate coating preceding the outer enteric layer. This method has important advantages over the methods described in the patent literature and mentioned above, allowing, as indicated, to obtain omeprazole tablets with adequate stability when performing fewer operations and using less equipment than the procedures already described.

However, the preparation is not simple due to the crystalline nature of the amino acids used. In addition, such tablets typically have unfavorable characteristics with respect to hardness and brittleness.

Thus, there is still a need for pharmaceutical compositions containing omeprazole, having increased resistance to pH and moisture, and not associated with the above disadvantages (production complexity and the use of complex equipment, high production costs), and also allowing to obtain pharmaceutical compositions with properties improved compressibility.

The objective of the invention is to provide a simple, fast and economical method for producing pharmaceutical compositions containing omeprazole.

Another objective of this invention is to provide a method for producing pharmaceutical compositions in the form of tablets containing omeprazole, stable against pH and moisture, as well as under storage conditions.

Another objective of this invention is to provide a method for producing pharmaceutical compositions in the form of tablets containing omeprazole and amino acids having good compressibility.

Finally, another objective of the present invention is the creation of pharmaceutical compositions in the form of tablets containing omeprazole, with good compressibility, stable against. pH and moisture, as well as storage conditions.

These objectives are achieved by the method of the present invention. Unexpectedly, the possibility of obtaining pharmaceutical compositions in the form of tablets containing omeprazole or its salts and a basic amino acid in crystalline form selected from the group of L-arginine, L-lysine and L-histidine; such compositions have good pH and moisture resistance of omeprazole and also have satisfactory compressibility characteristics, which was achieved by wetting and then drying the basic amino acid to a residual water content of less than 0.75% and then adding sodium alginate.

The method of the present invention includes two different, essentially important stages.

The first stage is a morphological external modification of the particle of the amino acid to obtain tablets without violating its crystalline form by wetting and subsequent drying of the particle. It was unexpectedly discovered that such a modification is achieved by a simple step consisting in the inclusion of water in a total amount of less than 0.75 wt.% Of the amino acid.

Another step is the addition of sodium alginate with a low thickening ability and low water content. Thus, only by including one excipient are several functions introduced that contribute to the stabilization of omeprazole.

Brief Description of the Figures

Figures 1 (A) and 1 (B) are photographs of images of particles of L-arginine before and after processing, obtained by electron microscopy.

Figure 2 shows the X-ray diffraction spectra of a sample of L-arginine without treatment and after treatment by wetting and subsequent drying.

The present invention relates to a method for producing stable pharmaceutical compositions in the form of tablets containing omeprazole, sodium alginate and a basic amino acid selected from the group L-arginine, L-lysine and L-histidine, comprising the steps of:

a) preliminary modification of the surface morphology of the basic amino acid by wetting and subsequent drying to a residual water content of less than 0.75 wt.% by weight of the amino acid;

b) incorporating a basic amino acid into a preformed granulate containing omeprazole and low moisture sodium alginate;

c) inclusion of the remaining excipients to obtain granulate;

d) grinding the granulate from step c) until a uniform particle size distribution is obtained; and

e) the inclusion of a lubricant, the implementation of the tabletting process and the application of an enteric coating on the resulting tablets.

In industry, there is a general need for both active pharmaceutical compounds and excipients processed by methods that produce products with adequate properties that can be easily handled on an industrial scale and that have good storage stability. Such features make pharmaceutical compounds and excipients suitable for pharmaceutical preparations. In order to obtain the appropriate composition, it is useful and important that not only the active substance, but also all the components of the composition are obtained and presented in the most suitable form.

That is why it was unexpectedly discovered that by subjecting the basic amino acids to the process of wetting and subsequent drying to a residual water content of less than 0.75 wt.% By weight of the amino acid, a partial modification of the surface morphology of the crystals of the basic amino acid is obtained without disturbing its crystalline state.

This can be easily seen in figures 1 (A) and 1 (B). The wetting procedure allows to achieve surface modification in the structure of the basic amino acid by erosion, which leads to an increase in porosity and deformation of the particles.

However, although such surface changes occur, the crystalline structure of the amino acid does not change significantly, which can be seen on the X-ray diffraction spectra obtained before and after processing by wetting and subsequent drying (Figure 2). As can be seen in figure 2, the spectrum does not change significantly, which indicates that the crystal structure remains the same after the particles undergo the specified process. Therefore, the modification of particles is only surface, and only porosity and surface deformation increase.

It should be noted that this modification is achieved by obtaining particles of an amino acid with a final residual moisture content of less than 0.75 wt.% By weight of the amino acid.

Such a wetting process can be carried out by spraying or in a fluidized bed.

It is known in the art and also indicated in the literature that “no substance is less compressible than a fully crystalline material” (Shangraw Ralph F., Pharmaceutical Dosage Forms, pgs 225, Editorial Marcel Dekker); and, as mentioned earlier, it is important that all components in the composition are in the most favorable condition. For this reason, without going into theory, it is believed that such a change in the surface structural morphology of the particles of the used amino acid acquires morphological characteristics that are more suitable for producing tablets containing omeprazole with desirable compressibility.

Another distinctive step of the method of the present invention is the addition of sodium alginate with low thickening ability and low water content. Alginic acid and its sodium salt are linear copolymers of β (1-4) -D-mannuronic acid and α-L-guluronic acid. They may have different morphologies and also different molecular weights. The molecular weight can range from 20,000 to 200,000. Such characteristics give each of them special properties.

The addition of sodium alginate to tablets produced by the method of the present invention includes several functions; some of them contribute to the stabilization of omeprazole. These include the functions listed below.

1. Dehydrating activity due to their ability to bind water or moisture. It is well known and described in the literature (Handbook of Pharmaceutical Excipients (1994), pp. 428-429) that sodium alginate is slightly soluble in water, but readily attaches water to form gels and removes moisture or water from the medium. Sodium alginate has an almost neutral pH. In a 1% solution, the pH is about 7.2. It is stable at pH 4 to 10, but it easily captures protons from the medium, turning into alginic acid at pH 4.

In the case of the formation of alginic acid due to its insolubility, the availability of free protons in the medium decreases. In addition, alginic acid formed under such conditions also contributes to the dehydration of the medium due to its ability to absorb water in an amount equivalent to 200-300 body weight (Handbook of Pharmaceutical Excipients (1994), pp. 10-11).

2. Binding and destructive activity. Upon receipt of the tablets, sodium alginate can be used as a binder, as well as a decomposition aid (Sakr AM, Elsabbagh HM, Shalaby A.N., Effect of the technique of incorporating sodium alginate on its binding and / or disintegrating effectiveness in sulphathiazole tablets, Pharm. Ind. (1978); 40 (10); 1080-1086). At concentrations above 2%, due to its ability to absorb water, it acts as a decomposition agent (Esezobo S., Disintegrants: effects of interacting variables on the tensile strengths and disintegration times of sulphaguanidine tablets. Int. J. Pharmaceutics (1989); 56: 207 -211). At concentrations up to 10%, it is usually used in tablets that dissolve with the release of bubbles, as well as for changing the release rate of active components (Klaudianos S., Alginate sustained-action tablets, Dtsch Apoth Zig (1978); 118: 683-684 )

It was experimentally found that when receiving tablets with omeprazole, it is desirable that, when using sodium alginate, the conditions indicated below are met.

a. The content of sodium alginate should be less than 15%, preferably from 8 to 12%. If the percentage of sodium alginate is higher, the preparation of tablets is difficult and may affect the release of omeprazole due to gel formation. Higher concentrations (20-50%) are used in the preparation of controlled release tablets.

b. The moisture content in sodium alginate should be less than 2%. The literature describes alginates suitable for pharmaceutical use containing up to 15% water, as determined by weight loss upon drying. It is shown that such alginates are not suitable for the method of the present invention due to the inconvenience associated with stability. The maximum acceptable water content, which gives satisfactory experimental results in the method of the present invention, corresponds to a value of less than 2%. Pre-vacuum drying at 70 ° C of commercial alginates makes alginate with a suitable moisture content easily accessible.

Other properties important that sodium alginate must satisfy in the process of the invention are listed below.

from. The molecular weight of sodium alginate should be low.

d. Preferably, the particles in morphology should be granules.

e. It should have the ability to form aqueous solutions (at a content of 1%) with low viscosity (20-100 cPs).

Among commercial sodium alginates, not limited to, satisfactory, as shown, is the so-called MANUCOL LB (available from KELCO ALGINATOS).

One of the advantages obtained in the method of this invention when adding sodium alginate, due to the properties of the alginate described previously, is that the number of required components for stabilizing omeprazole indicated in the patent literature is reduced.

In addition, the addition of sodium alginate reduces the number of operations and the amount of equipment used in the industrial production of tablets with omeprazole.

The drying stages of both sodium alginate and the processed L-arginine are considered critical because they can affect the stability of omeprazole. It was found that the optimal final residual moisture from drying should be less than 2% for sodium alginate and less than 0.75% for L-arginine.

Each tablet obtained in accordance with the method of the present invention in the examples below shows adequate compressibility, excellent stability and suitable pharmaceutical characteristics.

The invention is further illustrated by the following examples, but is not limited to.

Example 1

Coated tablets with 20 mg omeprazole

Composition for 10,000 tablets.

Omeprazole 200 g Sodium Alginate 250 g L-Arginine 1750 g Sodium Lauryl Sulfate Powder 40 g Copolyvidone 150 g Magnesium stearate 15 g Talc 110 g Microcrystalline cellulose 485 g

250 g of sodium alginate is dried in vacuum at 70 ° C until a residual moisture content of less than 2% is obtained. At the same time, 1750 g of L-arginine is moistened by spraying 4300 ml of distilled water and dried to a residual moisture content of not more than 0.75% (Drying Balance Mettler LJ 16 Moisture Analyzer).

Both substances are individually sieved and mixed with omeprazole, magnesium stearate and talc in the amounts indicated in I. The resulting mixture is pressed (a Piccola rotary tableting machine) and ground (a cone mill with a Quadro Comil sieve) to achieve the appropriate particle size distribution.

Then, the obtained granulate is mixed with the indicated amounts of sodium lauryl sulfate, copolyvidone and microcrystalline cellulose. The mixture is compressed into 300 mg tablets (Piccola Rotary Tablet Machine).

The resulting tablets are coated with a suspension prepared from 360 g of a mixture of polyvinyl acetophthalate, talc, stearic acid, titanium dioxide and triethyl citrate (a mixture of the Opadry Enteric YP 6-7005 White type) dispersed in 2000 g of an alcohol: water mixture (14: 3) until gastroresistance is confirmed pills.

Gastroresistance is determined according to the method specified in USP 24.

Example 2

Composition for 10,000 tablets.

Omeprazole 200 g Sodium Alginate 500 g L-Arginine 2000 g Sodium Lauryl Sulfate Powder 40 g Hydroxypropyl methylcellulose 250 g Magnesium stearate 75 g Talc 120 g Lactose, anhydride. 1815 g

500 g of sodium alginate is dried in vacuum at 70 ° C until a residual moisture content of less than 2% is obtained. At the same time, 2000 g of L-arginine is moistened by spraying or in a fluidized bed 5000 ml of distilled water and dried to obtain a residual moisture content of not more than 0.75% (Drying Balance Mettler LJ 16 Moisture Analyzer).

Both substances are individually sieved and mixed with 200 g of omeprazole, 25 g of magnesium stearate and 120 g of talc. The resulting mixture was pressed (a Piccola rotary tableting machine) and ground (a Quadro Comil cone mill) to achieve an appropriate particle size distribution.

Then, the obtained granulate is mixed with the indicated amounts of sodium lauryl sulfate, hydroxypropyl methylcellulose, lactose anhydride and the remaining amount of magnesium stearate. The mixture is compressed into 500 mg tablets (Piccola Rotary Tableting Machine).

The tablets obtained are coated from a suspension prepared from 360 g of a mixture of polyvinyl acetophthalate, talc, stearic acid, titanium dioxide and triethyl citrate (a mixture of the Opadry Enteric YP 6-7005 White type) dispersed in 2040 g of an alcohol: water mixture (14: 3), before confirmation of gastroresistance of tablets.

Gastroresistance is determined according to the method specified in USP 24.

Example 3

Coated tablets with 40 mg omeprazole

Composition for 10,000 tablets

Omeprazole 400 g Sodium Alginate 250 g L-Arginine 1750 g Sodium Lauryl Sulfate Powder 40 g Copolyvidone 150 g Magnesium stearate 15 g Talc 110 g Microcrystalline cellulose 285 g

250 g of sodium alginate is dried in vacuum at 70 ° C until a residual moisture content of less than 2% is obtained. At the same time, 1750 g of L-arginine is moistened by spraying or in a fluidized bed of 4300 ml of distilled water and dried to obtain a residual moisture content of not more than 0.75% (Drying Balance Mettler LJ 16 Moisture Analyzer).

Both substances are individually sieved and mixed with omeprazole, magnesium stearate and talc in the amounts indicated in the composition. The resulting mixture was pressed (a Piccola rotary tableting machine) and ground (a Quadro Comil cone mill) to achieve an appropriate particle size distribution.

Then, the obtained granulate is mixed with the indicated amounts of sodium lauryl sulfate, copolyvidone and microcrystalline cellulose. The mixture was compressed into 300 mg tablets (Piccola Rotary Tableting Machine).

The tablets obtained are coated with a suspension prepared from 360 g of a mixture of polyvinyl acetophthalate, talc, stearic acid, titanium dioxide and triethyl citrate (a mixture of the Opadry Enteric YP 6-7005 White type) dispersed in 2000 g of an alcohol: water mixture (14: 3), before confirmation of gastroresistance of tablets.

Gastroresistance is determined according to the method specified in USP 24.

Example 4

Coated tablets with 20 mg of omeprazole in the form of magnesiumomeprazole

Composition for 10,000 tablets

Omeprazole (as Magnomeprazole) 200 g Sodium Alginate 250 g L-Arginine 1750 g Sodium Lauryl Sulfate Powder 40 g Copolyvidone 150 g Magnesium stearate 15 g Talc 110 g Microcrystalline cellulose 485 g

250 g of sodium alginate is dried in vacuum at 70 ° C until a residual moisture content of less than 2% is obtained. At the same time, 1750 g of L-arginine is moistened by spraying or in a fluidized bed of 4300 ml of distilled water and dried to obtain a residual moisture content of not more than 0.75% (Drying Balance Mettler LJ 16 Moisture Analyzer).

Both substances are individually sieved and mixed with omeprazole, magnesium stearate and talc in the amounts indicated in the composition. The resulting mixture was pressed (a Piccola rotary tableting machine) and ground (a Quadro Comil cone mill) to achieve an appropriate particle size distribution.

Then, the obtained granulate is mixed with the indicated amounts of sodium lauryl sulfate, copolyvidone and microcrystalline cellulose. The mixture was compressed into 300 mg tablets (Piccola Rotary Tableting Machine).

The tablets obtained are coated with a suspension prepared from 360 g of a mixture of polyvinyl acetophthalate, talc, stearic acid, titanium dioxide and triethyl citrate (a mixture of the Opadry Enteric YP 6-7005 White type) dispersed in 2000 g of an alcohol: water mixture (14: 3), before confirmation of gastroresistance of tablets.

Gastroresistance is determined according to the method specified in USP 24.

Claims (6)

1. A method for producing stable pharmaceutical compositions in the form of tablets containing omeprazole and a basic amino acid, characterized in that sodium alginate is added and the method comprises the following steps: a) preliminary modifying the surface morphology of the basic amino acid by wetting and subsequent drying to a total residual water content less than 0.75 wt.% by weight of amino acids; b) incorporating a basic amino acid into a preformed granulate containing omeprazole and sodium alginate with a moisture content of less than or equal to 2%; c) inclusion of the remaining excipients until granulate is obtained; d) grinding the granulate from step e) to obtain a uniform particle size distribution; e) the inclusion of a lubricant, the implementation of the tabletting process and the application of the resulting tablets intersolubility coating. 2. The method according to claim 1, characterized in that the content of sodium alginate is 15 wt.% By weight of the tablet, preferably 8-12 wt.%. 3. The method according to claim 1 or 2, characterized in that the sodium alginate used has a low molecular weight, the morphology of the particles is preferably granules, the moisture content is 1-2%. 4. The method according to claim 1, characterized in that the basic amino acid is L-arginine, L-lysine or L-histidine. 5. The pharmaceutical composition in the form of tablets obtained by the method according to claim 1, characterized in that it contains omeprazole in concentrations of 1-40 mg per tablet. 6. The pharmaceutical composition obtained by the method according to claim 1, characterized in that it contains magnesiumomeprazole or salts of omeprazole and alkali metals in amounts equivalent to the amount of omeprazole 10-40 mg per tablet.

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